Virus attenuation by genome-scale changes in codon pair bias

Science. 2008 Jun 27;320(5884):1784-7. doi: 10.1126/science.1155761.


As a result of the redundancy of the genetic code, adjacent pairs of amino acids can be encoded by as many as 36 different pairs of synonymous codons. A species-specific "codon pair bias" provides that some synonymous codon pairs are used more or less frequently than statistically predicted. We synthesized de novo large DNA molecules using hundreds of over-or underrepresented synonymous codon pairs to encode the poliovirus capsid protein. Underrepresented codon pairs caused decreased rates of protein translation, and polioviruses containing such amino acid-independent changes were attenuated in mice. Polioviruses thus customized were used to immunize mice and provided protective immunity after challenge. This "death by a thousand cuts" strategy could be generally applicable to attenuating many kinds of viruses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Animals
  • Antibodies, Viral / biosynthesis
  • Capsid Proteins / genetics*
  • Cloning, Molecular
  • Codon*
  • Cytopathogenic Effect, Viral
  • Genome, Viral*
  • HeLa Cells
  • Hot Temperature
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation
  • Poliomyelitis / immunology
  • Poliomyelitis / virology
  • Poliovirus / genetics*
  • Poliovirus / growth & development
  • Poliovirus / immunology
  • Poliovirus / pathogenicity*
  • Poliovirus Vaccines* / genetics
  • Poliovirus Vaccines* / immunology
  • Protein Biosynthesis
  • Vaccination
  • Vaccines, Attenuated / genetics
  • Vaccines, Attenuated / immunology
  • Viral Plaque Assay
  • Virulence


  • Antibodies, Viral
  • Capsid Proteins
  • Codon
  • Poliovirus Vaccines
  • Vaccines, Attenuated